This invention relates to novel proline derivatives having antihypertensive activity. More specifically, the invention pertains to 1-(3-mercapto-2-methylpropanoyl)prolyl amino acid derivatives, processes for preparation thereof, and to use of these derivatives as antihypertensive agents.
Recently, Ondetti et al. synthesized various mercaptoalkanoyl amino acids and tested them in vitro for the inhibition of angiotensin I-converting enzyme. Based on this work, they reported that 1-(D-3-mercapto-2-methylpropanoyl)-L-proline (which they termed "SQ-14225") is a particularly good inhibitor of angiotensin I-converting enzyme [Biochemistry, 16, 5484 (1977)]. Ondetti et al. also investigated SQ-14225 and related compounds, and reported that SQ-14225 also has a potent inhibitory activity in vivo on angiotensin I-converting enzyme, and shows superior antihypertensive activity in experimental hypertensive animals based on its inhibitory action [Science 196, 441 (1977)]. U.S. Pat. No. 4,046,889 and DT-OS No. 2,703,828 to Ondetti et al. disclose SQ-14225 and related compounds.
We have made extensive investigations in order to find out pharmacologically better derivatives of SQ-14225 and related compounds, and found that formation of a new peptide bond by introduction of a certain amino acid into the carboxyl group of the proline moiety of SQ-14225 or its derivatives yielded desirable compounds which show a milder onset of antihypertensive activity and a longer duration of such activity than SQ-14225 or its derivatives.